Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism

eLife

Giovanny Rodriguez Blanco¹  Alex von Kriegsheim¹  Tim Young²  Dylan Gerard Ryan²  Efterpi Nikitopoulou²  Ming Yang²  Marc Segarra-Mondejar²  Christian Frezza²  Christopher A Powell³  Nils Burger³  Jan Lj Miljkovic³  Michael P Murphy³  Michal Minczuk³  Hiran A Prag⁴ 

[1] Edinburgh Cancer Research UK Centre, Institute of Genetics and Cancer, Edinburgh, United Kingdom;MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom;MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom;MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom;Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom;

关键词: TCA cycle;    mitochondria;    metabolism;    metabolomics;    Mouse;   

DOI  :  10.7554/eLife.72593

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The Tricarboxylic Acid (TCA) Cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology, and amino acid homeostasis.

【 授权许可】

CC BY